The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are used in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to posess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs xcexcxe2x80x2 receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 agonists.
Recently, a non-peptidic xcex4 agonist, BW 373U86, was described by Chang et al., 1993, J. Pharmacol. Exp. Ther., 267: 852-857., as the first xcex4-selective non-peptide with analgesic activity, however, it shows significant affinity for the xcexc receptor.
Thus, the problem underlying the present invention was to fund new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
In WO 93/15062 and WO 95/045051, some diarylmethylpiperazine and diarylmethylpiperidine compounds, including BW 373U86, are disclosed, but these prior art compounds are structurally distinct from the compounds according to the present invention.
The problem mentioned above has been solved by developing novel piperazine and piperidine compounds, as will be described below.
The novel compounds according to the present invention are defined by the formula (I) 
wherein
G is a carbon atom or a nitrogen atom;
A is selected from
(i) phenyl substituted by any of xe2x80x94COOH, xe2x80x94CONH2, COOCH3, xe2x80x94CN, NH2 or xe2x80x94COCH3;
(ii) naphtyl, benzofuranyl, and quinolinyl; and 
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, ( CH2)oCH3(CH2)oSOR7, (CH2)oSO2R7 and (CH2)oSO2NR7R8 wherein o is 0, 1, or 2, and R7 and R8 are as defined below;
R1 is selected from hydrogen; a branched or straight C1-C6 alkyl, C1-C6 alkenyl, xe2x80x94CO(C1-C6 allyl); (C1-C6 alkyl)-B wherein B is as defined below; C3-C8 cycloallyl, C4-C8 (alkyl-cycloalcyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; C6-C10 aryl; and heteroaryl having from 5-10 atoms selected from any of C, S, N and O; and whereby the C6-C10 aryl and the heteroaryl may optionally be substituted by 1 or 2 substituents selected from hydrogen, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, (CH2)oCH3(CH2)oSOR7, (CH2)oSO2R7 and (CH2)oSO2NR7R8;
wherein o is 0, 1, or 2, and R7 and R8 are as defined below:
R7 and R8 is each and independently as defined for R1 above;
R2 is selected from hydrogen, CH3, OR1, CO2R1, and CH2CO2R1 wherein R1 is as defined above;
R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, is each and independently as defined for R1 above;
B is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety, each having from 5 to 10 atoms selected from any of C, S, N and O, and each being optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCOR7, (CH2)pCO2R7, OR7, (CH2)pSOR7, (CH2)pSO2R7, and (CH2)pSO2NR7R8;
wherein p is 0, 1, 2 or 3 and wherein R7 and R8 are as defined above;
R3, R4, R5 and R6 is each and independently selected from R7, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8, (CH2)pCO2R7, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR7, and (CH2)pOR7;
wherein p is 0, 1, 2, 3, or 4, and R7 and R8 are as defined above;
with the proviso that when A is a phenyl ring substituted by a xe2x80x94CN group or by a xe2x80x94NH2 group, B may not be 
xe2x80x83wherein
Z1 is hydroxy, and esters thereof;
hydroxymethyl, and esters thereof; or
amino, and carboxamides and sulfonamides.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula (I) wherein
G is a carbon atom or a nitrogen atom;
A is selected from
(i) phenyl substituted by any of xe2x80x94COOH, xe2x80x94CONH2, COOCH3, xe2x80x94CN, NH2 or xe2x80x94COCH3;
(ii) naphtyl, benzofuanyl, and quinolinyl; and 
wherein the phenyl ring of each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from hydrogen, CH3, (CH2)oCF3, halogen, CONR7R8, CO2R7, COR7, (CH2)oNR7R8, (CH2)oCH3(CH2)oSOR7, (CH2)oSO2R7 and (CH2)oSO2NR7R8, wherein o is 0, 1, or 2, and R7 and R8 are as defined below;
R1, R7 and R8 is each and independently selected from hydrogen; a branched or straight C1-C4 alkyl, allyl, xe2x80x94COxe2x80x94(C1-C6 alkyl); (C1-C6 alkyl)-B wherein B is as defined below; C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; and phenyl;
R2 is hydrogen, methyl, or OR1 wherein R1 is as defined above;
R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, is each and independently as defined for R1 above;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and 
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH3, CF3, halogen, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCOR7, (CH2)pCO2R7, and OR7;
wherein p is 0 or 1, and wherein R7 and R8 are as defined above; and
R3, R4, R5 and R6 is each and independently selected from hydrogen, CH3, CH(Me)2, CH2CH(Me)2, CH(Me)CH2CH3 (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8, (CH2)pCO2R7, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR7, and (CH2)pOR7, wherein p is 0, 1, 2, or 3, and wherein R7 and R8 are as defined above;
with the proviso that when A is a phenyl ring substituted by a xe2x80x94CN group or by a xe2x80x94NH2 group, B may not be 
xe2x80x83wherein
Z1 is hydroxy, and esters thereof;
hydroxymethyl, and esters thereof; or
amino, and carboxamides and sulfonamides.
Especially preferred compounds according to the invention are compounds of the formula (I) wherein
G is a nitrogen atom;
A is selected from 
wherein
R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 is each an ethyl group;
R1 is selected from hydrogen, mnethyl, ethyl, allyl, or CH2-cyclopropyl;
R2 is H, methyl, or OR1, wherein R1 is as defined above;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and 
each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, methyl, CF3, halogen, (CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCOR7, (CH2)pCO2R7, and OR7,
wherein p is 0, 1, or 2, and wherein R7 and R8 are as defined for R1 above;
R3, R4, R5 and R6 is each and independently selected from H, CH3, CH(Me)2, CH2CH(Me)2, CH(Me)CH2CH3(CH2)pCONR7R8, (CH2)pNR7R8, (CH2)pCONR7R8, (CH2)pCO2R7, (CH2)pPh, (CH2)p(p-OH Ph), (CH2)p-3-indolyl, (CH2)pSR7, and (CH2)pOR7 
wherein p is 0, 1 or 2, and wherein R7 and R8 are as defined above;
The substituents A and B respectively, may optionally be substituted at any position of the ring.
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having from 6-10 carbon atoms, such as phenyl and naphtyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9chydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.
By xe2x80x9cheterohydroaromaticxe2x80x9d we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such the resulting biotransformation product of the derivative is the active drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated.
The novel compounds of the present invention are useful in therapy, especially for the treatment of pain.
The compounds are also useful for modulating the analgesic effects acting at the xcexc opioid receptor subtype, the modulation of side effects seen with agents acting at the xcexc opioid receptor subtype such as morphine, especially respiratory depression, gut motility and abuse liability.
Compounds of the invention are also useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
The best mode of performing the present invention known at present, is to use the compounds according to Example 21 (compound 33), Example 22 (compound 34), Example 23 (compound 37), Example 24 (compound 38), Example 25 (compound 41), Example 26 (compound 42), Example 27 (compound 45), Example 29 (compound 51), Example 30 (compound 54), Example 35 (compound 64), Example 36 (compound 65), Example 50, and Example 51. The numbering of the compounds is in accordance with the Examples below, as well as in accordance with the numbering in the Schemes presented in the following.
Methods of Preparation
Generalized Method A
An aldehyde or ketone is treated with a nucleophile such as a Grignard or organolithium species to produce the corresponding alcohol. This alcohol may then be converted into a suitable leaving group (X) such as an ester, sulphonate or halide which may in turn be displaced with a nucleophilic species such as a substituted or unsubstituted piperazine. N-(4)-unsubstituted piperazine derivatives may then be suitably substituted with a variety of groups via their organo halide or equivalent species, or acylated with a number of different acylating compounds. This sequence of events will give rise to compounds according to general formula I.
Generalized Method B
An N-protected amino acid, as its activated ester, may be reacted with a second amino acid ester. On treatment with an acid this species may then cyclize to form a piperazinedione. This dione may be reduced via a number of standard methods to the corresponding piperazine (e.g. a reducing agent such as lithium aluminium hydride, by conversion to the thioamide and subsequent desulphurization, hydrogenation in the presence of POCl3 etc.) This piperazine may then be alkylated or acylated on one or more of the nitrogens and/or may be used subsequently in generalized method A.
Deprotection of functional groups or further modifications may then be necessary, these are described for each individual case. Specific examples for the above transformations are given in the experimental.
All transformations contemplated use reagents (including salts) and solvents known to the art of chemistry and to biotransformations carried out in a suitable biological medium to bring about these transformations and includes all reaction enhancing agents (e.g. HMPA), and chiral resolutions using chiral salt formation and chiral biological resolutions.
The invention will now be described in more detail by the following examples, which are not to be construed as limiting the invention. 